Function of CD19 in B-cell Development &Differentiation

Burnham Institute For Medical Research, La Jolla CA

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Abstract

DESCRIPTION (provided by applicant): B cell activation is initiated by tyrosine phosphorylation of proximal cytosolic and membrane bound adaptor proteins to allow branching of signaling pathways, such as the phosphatidylinositol 3-kinase (PI3K) pathway. Phosphoinositide metabolism is thought to be of key importance to aspects of B cell activation, proliferation, differentiation and survival. PI3K activity is induced by the BCR and amplified by p85alpha recruitment to CD19 and perhaps other cytosolic adaptor proteins. Phosphatidylinositol-3,4,5-trisphosphate (PIP3,4,5) is generated by PI3K in activated cells, leading to the recruitment of pleckstrin-homology (PH)-containing proteins and conformation induced activation of other binding partners, Excessive production of PIP3,4,5 leads to autoimmunity or transformation and is tightly regulated by the inositol phosphatases PTEN and SHIP. The overall goal of this renewal is to understand the context of PIP3,4,5 regulation in B cell differentiation and maintenance. Central to this goal is a detailed understanding of phosphoinositide metabolism in B cells with a particular focus on the opposing enzymatic activities of PI3-kinase, PTEN and SHIP in regulating levels of PIP3,4, 5 and its incumbent role in the recruitment and activation of signaling intermediates. CD19 is the primary activator of PI3K in B cells, leading to the production of PIP3,4 and PIP3,4,5, while the inositol phosphatase PTEN acts to attenuate PIP3,4,5 accumulation by conversion to PIP4,5. Fc-gamma-RIIB1 (CD32) can also attenuate PIP3,4,5 levels through the recruitment of SHIP phosphatase, which converts PIP3,4,5 to PIP3,4. These findings suggest an interplay of CD19 and CD32 function focused on the regulated production of PIP3,4,5 and its ability to recruit and activate downstream effectors. Herein we explore the molecular basis and physiologic significance of CD19 and CD32 function in the regulated production of PIP3,4, PIP4,5 and PIP3,4,5 as key secondary messengers to effect cell fate.